Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09203
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Legal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: UNUMA Kana 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (30586425)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: LPS / autophagy / hepatocyte / mitochondria / lysosomal exocytosis; / 敗血症

Outline of Final Research Achievements

In this study, in the liver of sepsis, elimination of damaged mitochondria through the autophagy-lysosome system and increased appearance of mitochondrial DNA in plasma were confirmed. Moeover, we provide evidence for the secretion of mitochondrial proteins and DNA from lipopolysaccharide (LPS)-stimulated rat hepatocytes as well as mouse embryonic fibroblasts (MEFs). The secretion of mitochondrial contents is accompanied by the secretion of proteins that reside in the lumenal space of autolysosomes, but not by a lysosomal membrane protein. The pharmacological inhibition of autophagy and Atg5(-/-) MEFs blocks the secretion of mitochondrial constituents from LPS-stimulated cells. Furthermore, we show that direct exposure of purified mitochondria activates polymorphonuclear leukocytes, as evident by the induction of IL1B/interlekin-1β, a pro-inflammatory cytokine.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

これまで、敗血症病態のヒト血漿中でミトコンドリアに豊富に存在するタンパク発現が増加することなどは知れていたが、多くは逸脱と考えられていた。本研究では、単離白血球に精製ミトコンドリアを曝露したところ、炎症性サイトカインが産生されたことや、細胞膜が破綻しない段階で細胞外に障害ミトコンドリアが確認されたことから、その一部が能動的なメカニズムを介していることが明らかにすることができたのは学術的意義があることと考える。